De novo substitutions of TRPM3 cause intellectual disability and epilepsy

David A Dyment; Paulien A Terhal; Cecilie F Rustad; Kristian Tveten; Christopher Griffith; Parul Jayakar; Marwan Shinawi; Sara Ellingwood; Rosemarie Smith; Koen van Gassen; Kirsty McWalter; A Micheil Innes; Matthew A Lines

doi:10.1038/s41431-019-0462-x

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Eur J Hum Genet. 2019 Oct;27(10):1611-1618. doi: 10.1038/s41431-019-0462-x. Epub 2019 Jul 5.

Authors

David A Dyment^{1

2}, Paulien A Terhal³, Cecilie F Rustad⁴, Kristian Tveten⁵, Christopher Griffith⁶, Parul Jayakar⁷, Marwan Shinawi⁸, Sara Ellingwood⁹, Rosemarie Smith⁹, Koen van Gassen³, Kirsty McWalter¹⁰, A Micheil Innes¹¹, Matthew A Lines^{12

13}

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
² Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
³ Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
⁴ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁵ Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
⁶ University of South Florida, Tampa, FL, USA.
⁷ Nicklaus Children's Hospital, Miami, FL, USA.
⁸ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁹ Department of Pediatrics, Division of Genetics, Maine Medical Center, Portland, ME, USA.
¹⁰ GeneDx, Gaithersburg, MD, USA.
¹¹ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada. mlines@cheo.on.ca.
¹³ Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada. mlines@cheo.on.ca.

Abstract

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

MeSH terms

Adolescent
Alleles
Child
Child, Preschool
Epilepsy / diagnosis*
Epilepsy / genetics*
Facies
Female
Genetic Association Studies*
Humans
Intellectual Disability / diagnosis*
Intellectual Disability / genetics*
Male
Models, Molecular
Mutation*
Phenotype*
Protein Conformation
Severity of Illness Index
TRPM Cation Channels / chemistry
TRPM Cation Channels / genetics*

Substances

TRPM Cation Channels
TRPM3 protein, human